415 THE METABOLIC EFFECT OF ENEMA TA OF ALCOHOL, DEXTROSE AND LE VULOSE IN HUMANS By THORNZ, M. CARPZNTBR NUTRITION LABORATORY OF THU CARNEGIS INSTITUTION OF WASHINGTON, BOSTON, MASS. Communicated April 28, 1926 The usual path of ingestion of food and drugs by man is by way of the mouth. Under some conditions','' such as congenital or accidental obstruction of the alimentary canal, unconsciousness, anesthesia or unwillingness of the individual to cooperate (insanity), it is necessary to resort to other paths of ingestion. Those commonly used are the intravenous, subcutaneous, intraperitoneal and rectal injections of the substance needed or under observation. Any study of the metabolic effect of one of these methods of ingestion has therefore a practical significance, as it results in an increased knowledge regarding the effectiveness of the method. Such an investigation has another interest. It is conceivable that when a substance is introduced into the circulation directly or ingested at a different point in the alimentary canal (e.g., the rectum), its path of distribution may be different than when the ingestion is by mouth, and the character and speed of metabolism may also be altered. This communication has to deal with the effects of enemata of ethyl alcohol, dextrose and levulose upon the metabolism of humans observed in an investigation which began as a part of the program' of study of the Nutrition Laboratory on the physiological and psychological effects of ethyl alcohol. Other experiments were added in order to include for comparative purposes the effect of rectal injection of solutions of dextrose and levulose. The subjects were four medical students presumably in good health. Problems studied were how completely and rapidly the materials were absorbed, what effect, if any, the absorption of these materials had upon the volume and some constituents of the urine, whether the pulse-rate was changed and to what extent the material absorbed was metabolized as indicated by a study of the respiratory exchange. The last was the chief problem of the investigation. The interpretation of the results depended in the main upon the course of the respiratory quotient. The respiratory quotient is the relation by volume of the carbon dioxide eliminated to the oxygen absorbed when a substance is oxidized. For the utilization of fat the value is 0.713, for carbohydrate 1.00 and for the portion of protein oxidized in the body it is 0.81. The respiratory quotient of alcohol is lower than any of these, namely, 0.667, so that if alcohol is metabolized in the body in such a manner that no other exeretory products
416 PHYSIOLOGY: T. M. CARPENTER PROC. N. A. S. are formed than carbon dioxide and water,'the result will be a lower respiratory quotient than that existing before alcohol was ingested. That this occurs when alcohol is given by mouth has been shown by a previous investigation in this Laboratory.2 Oxidation of dextrose or levulose, on the other hand, gives a respiratory quotient of 1.00 and ingestion by mouth results in a rise in the respiratory quotient,3 the greater and quicker change coming after the taking of levulose. The absorption of the substances used in the enemata of the present study was determined indirectly; that is to say, after a solution had been retained a given time in the rectum and large intestine, a cleansing enema was given to remove the unabsorbed material, and to be sure that this removal was complete, two and sometimes three such enemata were used. The amounts of the unabsorbed substance thus secured were then determined by suitable chemical methods. Urine was collected in the period before an experiment (preliminary) and for the time' just prior to and following the rectal injection (experimental). The volume, total nitrogen and chlorides were determined for these urines. When alcohol was injected, the amount eliminated by the kidneys was also estimated. In a number of speci'al experiments, the urine was collected in short periods. Determination of the alcohol content of these urines was expected to throw light on the metabolism of alcohol. For comparison purposes there were a few experiments in which similar amounts and concentrations of alcohol were taken orally and the alcohol determined likewise in the urine collected in short periods. The pulserate was taken periodically in all experiments in which the respiratory exchange was measured. The latter was determined by means'of the gasometer method, in which the expired air is separated from'the inspired air by valves and the expired air is' collected in a gasometer and analyzed. In several series of experiments a chamber4 respiration apparatus was used. A 0.6 per cent solution of sodium chloride was used alone in a number of experiments as a control solution to determine the effect of rectal injection of a liquid upon the several physiological and chemical processes. Ethyl alcohol is very rapidly and nearly cdmpletely absorbed when given in enematia. In 31'experiments in which quantities of alcohol varying from 11.0 grams in 220 cc. of 5 per cent solution to 60.8 grams in 810 cc. of 7.5'sblution were injected, there were only two cases in which the absorption was not better'than 98 per cent, and in these two instances the duration of the periods 'during which the solution was retained was 1 hour and 4 minutes, and 2 hours and 3 minutes. Alcohol was almost invariably found in the urines ccallected. The maximum amount eliminated in this manner was only 1.9 per cent of the alcohol given.' This occurred in one of the experiments in which urines were collected in short periods and as often as possible, after the giving of 37.5 -grams of alcohol in a 5 per cent solu-
417 tion, the collection lasting about 7 hours. The quantity of urine eliminated after alcohol was given was nearly always increased over that observed in the preliminary period before the experiment. In spite of this, the nitrogen and chloride eliminated were decreased after alcohol, the nitrogen slightly and the chloride to a more marked degree, indicating that the effect of the alcohol was to promote the elimination of water without removing other constituents of the, tissues at the same time. The most striking effect of the rectal injection of alcohol was the marked rise in pilse-rate. Previous researches of Dodge and Benedict,' Higgins2 and Miles6 have shown that the effect of alcohol is either to prevent the natural fall in pulse-rate, which would take place in the course of an experiment if no alcohol were given, or to produce a slight increase in the pulse-rate. In other words, there was usually a relative acceleration. This amounted to only a few beats at the most. In the experiments with rectal injection, however, the increases in pulse-rate were of much greater magnitude. The most marked effect observed was in a series with a sub-- ject who slept in a respiration chamber for the entire night after the rectal injection of 37.5 grams of alcohol in 500 cc. of water. In the five experiments of the series, the pulse-rate rose in the course of 6'/2 hours from an average level of 62 to an average of 73, and in an individual experiment it rose from 66 to 87 in 61/2 hours. Rectal injection of alcohol has a more specific influence upon the pulse-rate than the giving of like quantities by mouth. The respiratory exchange indicated very clearly a utilization of alcohol. The respiratory quotient began to lower within two hours after the rectal injection of alcohol and the greater the quantity of alcohol given, the more marked and persistent was this effect on the quotient. In the experiments by Higgins2 the decrease in the respiratory quotient commenced much sooner. Also in experiments in this research when alcohol was given by mouth, the respiratory quotient was lowered within one-half hour.' The studies of the urine, in which the alcohol elimination was determined by periods, indicated that the peak of concentration occurred at about the same time whether ingestion was by mouth or by rectum, that is, within the first hour and one-half, and that the alcohol disappeared from the urine in about the same length of time for equal quantities injected, i.e., 25 grams in about 5 hours, an average disappearance by various ways of 5 grams per hour. Calculated from the respiratory exchange and by means of Rosemann's formula,7 the maximum amount theoretically metabolized after rectal injection of alcohol was 4.4 grams per hour when 37.5 grams were given in 500 cc. of water. There is an unexplainable inconsistency in the results of the respiratory exchange measurements and the alcohol in urine determinations in that the respiratory quotient in these experiments re-
418 PHYSIOLOGY: T. M. CARPENTER IIPROC. N. A. S. mained much depressed at a time after the giving of alcohol when urine analysis would indicate a tendency for the alcohol to disappear. The solutions of dextrose and levulose in 5, 6 and 10 per cent concentrations were not so rapidly or so completely absorbed as similar solutions of alcohol which were retained for the same length of time. The maximum absorption of dextrose was 90 per cent in the case when 30 grams were given and the material injected was retained about 61/2 hours. The maximum amount absorbed per hour was 7.8 grams in a period of 21/4 hours. Levulose was, in general, absorbed slightly more rapidly than 'dextrose. The apparent absorptions are higher on the average than those for dextrose, several of them being over 90 per cent with a 5 per cent solution. When 50 grams in solution were retained 41/2 hours, an average of 10.4 grams per hour were absorbed. Indications from the results are that the rate of absorption of dextrose and levulose is greatest at first, and prolonging the time of retention of the material injected does not increase proportionately the amount of absorption. In the majority of experiments with dextrose the respiratory quotients were definitely raised, thus indicating an increased utilization of carbohydrate in the metabolism. The maximum increase in carbohydrate utilized calculated from the changes in the respiratory quotient was 4 grams per hour. If all of the carbohydrate utilized after the injection of dextrose was supplied by the dextrose absorbed, the absorption recorded would hardly suffice for more than two or three hours. If one considered only the increase in utilization of carbohydrate, the amount absorbed would be sufficient for a much longer time. On the other hand, the rectal injection of levulose does not, in the majority of cases, produce any marked rise in the respiratory quotient. This is in direct contrast to its effect when introduced by mouth. When it is introduced by mouth, it has a greater effect and produces a more prompt increase in the respiratory quotient than does an equal quantity of dextrose. Levulose, however, of all of the substances given by rectum, caused the greatest decrease in nitrogen elimination in the urine, indicating a sparing action upon the protein metabolism. This was not the case with dextrose, which had an effect upon the nitrogen in the urine about equal to that due to alcohol. Dextrose produced a greater increase in the volume of urine than did levulose while, on the other hand, dextrose had less effect upon the elimination of sodium chloride. In other words, with dextrose there were indications that the liquid injected and sodium chloride were eliminated while with levulose, the liquid injected and sodium chloride were retained. The results with alcohol, as well as with dextrose and levulose, indicate that the metabolism of materials introduced by rectum is different than that produced when they are given by mouth. The usual explanations
419 of the different effect of rectal injection upon metabolism are that the material is absorbed in such a manner that it goes directly into the systemic circulation and avoids the portal circulation and that differences observed in the results are due to the slowness of absorption. The first explanation seems untenable because all of the indications both from this work and from other researches are that the material passes high enough into the large intestine to be absorbed into the branches of the portal circulation and that consequently it must pass through the liver by means of the portal circulation. Experiments by others with small quantities of sugar given by mouth indicate that it was not the small quantity absorbed which produced the effects in question so that the slowness of absorption can hardly explain the results. From the results in this investigation it is believed that the material introduced by rectum passes into the portal circulation and through the liver and then throughout the body. As a hypothesis it is suggested that the liver, as well as the rest of the alimentary tract, under the conditions of the experiments is not in an active state so that the substance is metabolized throughout the body in a manner similar to the utilization of material in muscular work. Dextrose and alcohol are both substances which can be utilized in the body when given in enemata. A review of the earlier literature, the details of the experiments, a discussion of the practical applications and theoretical calculations, together with a suggested hypothesis, appear in Publication No. 369 of the Carnegie Institution of Washington. 1 Benedict and Dodge: Tentative Plan for a Proposed Investigation into the Physiological Action of Ethyl Alcohol in Man. Proposed Correlative Study of the Psychological Effects of Alcohol on Man. Privately printed, Boston, Massachusetts, 1913. See, also, Dodge and Benedict, Carnegie Inst. Wash. Pub., No. 232 (1915), pp. 266-275. 2 Higgins, Jour. Pharm. and Exper. Therap., 1917, 9, p. 441. 3 Benedict and Carpenter, Carnegie Inst. Wash. Pub., No. 261, 1918, pp. 240-246. 4 Benedict and Tompkins, Boston Med. and Surg. Jour., 1916, 174, pp. 857, 898 and 939. 5 Dodge and Benedict, Carnegie Inst. Wash. Pub., No. 232, 1915, p. 233. 6 Miles, Carnegie Inst. Wash. Pub., No. 333, 1924, p. 225. 7Rosemann, Oppenheimer's Handbuch d. Biochem., 1911, 4 (1), p. 423. ERRATA These PROCEEDINGS, pp. 335 ff., May, 1926. 3n 3n In equation (1), E should read E_.1 = 1 j=4.i 3n-b 3n-b in equation (2), should read j=4 in equation (3), vb) should read (b), and on page 337 "k the gas constant per gram" should read "k the gas constant per molecule."-e. 0. SALANT